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PURPOSE To evaluate the safety, maximum tolerated dose (MTD), and pharmacokinetics of patupilone administered once every 3 weeks with proactive standardized diarrhea management in patients with resistant or refractory ovarian, fallopian, or peritoneal cancer. PATIENTS AND METHODS Patients received patupilone (6.5 to 11.0 mg/m(2)) every 3 weeks via 20-minute infusion. Adverse events, dose-limiting toxicities (DLT), MTD, and tumor response were determined. The tumor response was measured by Response Evaluation Criteria in Solid Tumors (RECIST) and cancer antigen 125 levels. Results Forty-five patients were enrolled. Adverse events were mild to moderate in intensity, and grade 3 diarrhea (13%) was the most commonly reported serious adverse event. Grade 3 peripheral neuropathy was noted in two patients (4%). Diarrhea, peripheral neuropathy, and fatigue were the most common DLTs; however, these were uncommon in the first cycle and the MTD was therefore not reached in this study. Overall response (OR; complete and partial responses; median cycles, 8) per RECIST in patients with measurable disease (n = 36) was 19.5%. Median duration of disease stabilization (complete and partial responses and stable disease) was 15.8 months. These results appear improved from a previous study in a similar patient population using a weekly schedule (2.5 mg/m(2)/week; N = 53; OR, 5.7%). CONCLUSION Patupilone once every 3 weeks was well-tolerated at doses up to 11.0 mg/m(2). Patupilone demonstrated promising antitumor activity in patients with drug-resistant/refractory disease. An ongoing phase III study in this patient population is testing the 10.0 mg/m(2) dose.

Topotecan stabilizes the topoisomerase I (Topo I) cleavable complex. We measured Topo I levels in white blood cells of patients with ovarian cancer treated with topotecan. Topotecan was given i.v. daily x 5 q 3 weeks in combination with paclitaxel (1 day before topotecan) and cisplatin (just prior topotecan). Our aim was to correlate Topo I levels to pharmacokinetics and toxicity. Topo I levels were determined using Western blotting and were expressed relative to the Topo I level present in 10 microg cell lysate of the human IGROV1 ovarian cancer cell line. We found no correlation between Topo I levels and (non-)hematological toxicity. Topo I levels after the fifth topotecan infusion were significantly negatively correlated with the AUC of topotecan (R = -0.64, p = 0.026), in contrast with Topo I levels prior to (R = -0.25, p = 0.4) and after (R = -0.30, p = 0.3) the first topotecan infusion. Topo I levels after the fifth topotecan infusion (48 +/- 27%, mean +/- SD) were higher than Topo I levels prior to and after the first topotecan infusion (3.0 +/- 4.7 and 2.7 +/- 3.6%, respectively) (p = 0.001). In conclusion, we detected a significant inverse correlation between Topo I level and topotecan AUC at day 5, and we found increasing Topo I levels during a daily x 5 schedule of treatment with topotecan.

Aims: The feasibility, morbidity and toxicity of an intensified surgical treatment strategy consisting of aggressive cytoreductive surgery, intra-operative intraperitoneal perfusion of cisplatin and hyperthermia were evaluated in women with recurrent ovarian cancer., Methods: Five heavily pre-treated patients with extensive abdominal tumour bulk entered this pilot study. In all cases aggressive cytoreduction leaving tumour remnants <5 mm in diameter could be performed. This was followed intra-operatively by perfusion of the abdominal cavity with hyperthermic cisplatin 50-70 mg/m(2)for 90 min. During perfusion the intra-abdominal temperature was maintained at 40 degrees C. The median duration of surgery was 10 hours (range 9-11 hours)., Results: No major intra- or post-operative complications emerged. Median post-operative ileus (resuming of soft diet) was 11 days (9-13 days). The mean period of hospitalization was 25 days (range 17-42). Toxicity due to i.p. cisplatin was mainly metabolic and of grade 1-2, while no nephrotoxicity was observed. The pharmacokinetics of cisplatin indicated that the maximum concentration of cisplatin measured in the perfusate was 15 times higher than in plasma., Conclusions: We conclude that aggressive cytoreduction combined with hyperthermic intra-operative intraperitoneal cisplatin was feasible in a small group of heavily pre-treated ovarian cancer patients with extensive tumour bulk with acceptable morbidity and toxicity. Further studies are required in larger groups of patients to further establish the feasibility of this intensified treatment strategy. We stress that OVHIPEC is not a treatment modality on its own for advanced ovarian cancer. The effectiveness of OVHIPEC is likely to be dependent on the effectiveness of post-operative adjuvant chemotherapeutic regimens., (Copyright 2000 Harcourt Publishers Ltd.)

Purpose: Carboplatin doses are often determined by using modified Calvert formulas. It has been observed that the area under the concentration versus time curve (AUC) for free carboplatin is lower than expected when modified formulas are used for carboplatin/paclitaxel chemotherapy combination regimens. By using limited-sampling models, the carboplatin AUC actually reached can easily be verified, and the dose adjusted accordingly., Methods: In this report, we describe the development and validation of a limited-sampling model for carboplatin from 77 pharmacokinetic curves, when carboplatin is used in combination with paclitaxel., Results: The following single-point model was selected as optimal: AUC carboplatin (min mg(-1) ml(-1)) = 418. c(2.5 h)(mg/ml) + 0.43 (min mg(-1) ml(-1)), where c(2.5 h) is the concentration (mg/ml) of carboplatin 2.5 h after the start of a 30-min infusion. This model proved to be unbiased (mean prediction error = 3.4 +/- 1.6%) and precise (root mean square error = 10.1 +/- 1.5%)., Conclusions: The proposed model can be very useful for ongoing and future carboplatin/paclitaxel studies aimed to optimise and individualize treatment.

Background: In vitro data demonstrated a dose-response relationship for doxorubicin in ovarian cancer (OC) cell lines. However, this dose-response question for doxorubicin was never carefully addressed in OC patients. These data and the more favorable toxicity profile of the anthracycline analogue epirubicin prompted us to study high-dose epirubicin (HDE) in relapsed OC patients., Patients and Methods: This phase I study included 19 OC patients with measurable or evaluable disease and no more than one prior (cisplatin-containing) chemotherapy regimen. Dose escalation was not allowed in individual patients. Epirubicin was administered by rapid intravenous infusion (<5 min) once every 3 weeks and studied at the following dose levels: 120, 135, 150, 180 and 200 mg/m2 (at least 3 patients per dose level). None of the patients received hematopoietic growth factors. We defined the maximum tolerated dose (MTD) as the dose at which we observed WHO grade 4 hematologic toxicity in >/=50% and/or WHO grade 3 nonhematologic toxicity in >/=30% of the patients., Results: The MTD was 200 mg/m2, with DLT being both hematologic (leukopenia and/or thrombocytopenia) and nonhematologic (mucositis). Objective responses were observed in 6 patients (response rate 32%), 3 of them occurring in 10 patients with primary platinum resistance., Conclusions: HDE is tolerable and has activity in second-line after cisplatin-based chemotherapy in OC patients. The recommended dose for phase II trials in such patients is 150 mg/m2, with escalation to 180 mg/m2 if toxicity permits.

Aim: To investigate the pharmacokinetics of paclitaxel (Paxene) administered to patients with advanced breast or ovarian cancer and to document safety and anti-tumour activity in this study population., Patients and Methods: Patients with advanced breast or ovarian cancer were accrued to two clinical studies. Paclitaxel (Paxene) was administered as a 3-h 175 mg m-2 or as a 96-h 140 mg m-2(105 mg m-2 in the presence of liver metastases) infusion. Patients not responding to the 3-h schedule were permitted to cross-over to the 96-h schedule. The data were compared to those of five patients who were previously treated with paclitaxel administered as Taxol (140 mg m-296-h infusion) at our Institute., Results: Fourteen patients with breast cancer and five ovarian cancer patients were entered into this study. Seven patients received the 3-h regimen, and 12 were assigned to the 96-h schedule. Five patients originally treated with the 3-h schedule, crossed over to the 96-h arm. For the 3-h 175 mg m-2 dose, the area under the plasma concentration vs time curve (AUC) was (mean+/-SD) 16.9+/-4.8 h x micromol x l-1, whereas the AUCs were 5.5+/-1.2 and 4.3+/-0.9 h x micromol x l-1 for the 96-h 140 mg m-2 and 105 mg m-2 doses, respectively. The clearance of paclitaxel was independent of the dose in the 96-h group, indicating linear pharmacokinetics. Pharmacokinetics of Paxene (96-h 140 mg m-2) were not significantly different from the kinetics after Taxol (96-h 140 mg m-2) administration., (Copyright 1999 Academic Press.)

Purpose: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma., Patients and Methods: Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 microg/kg of G-CSF subcutaneously starting on day 6., Results: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease., Conclusion: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks.

Oxaliplatin [trans-1-diaminocyclohexane (DACH) platinum, L-OHP] was brought into clinical evaluation in ovarian cancer because of the in vitro and in vivo antitumour activity observed in experimental models resistant to cisplatin. The antitumour activity so far observed in phase II studies, in which L-OHP was mainly given at the dose of 130 mg/m2 as 2-hour infusion, ranged between 15% and 30% and has confirmed the preclinical data. These results strongly support the need for additional studies in patients with tumour primarily resistant to cisplatin to establish a role of L-OHP. Neurotoxicity, in the form of a peculiar sensory neuropathy, is the most important side effect, because it is cumulative after repeated administration of the single agent or of combinations with other highly active but neurotoxic antitumour drugs like taxanes and other platinum analogues. Further clinical development of L-OHP needs to take into account the characteristics of other available active drugs and the distinctive preclinical and clinical features of this DACH platinum complex.

This randomised controlled multicentre trial evaluated the effectiveness of recombinant human erythropoietin (rhEPO) in preventing anaemia and reducing the need for blood or erythrocyte transfusion in 122 ovarian cancer patients receiving platinum-based chemotherapy. The patients were randomly allocated to receive rhEPO 150 U/kg or 300 U/kg subcutaneously, three times a week, or open control. Patients also received up to 6 cycles of carboplatin or cisplatin, alone or in combination with other cytotoxic agents. Intention-to-treat analysis showed that 39.4% of patients in the control group received at least one blood transfusion, compared with 9.2% of patients treated with rhEPO. Patients treated with rhEPO experienced a significantly longer time to first erythrocyte transfusion than the control group and were less likely to experience nadir haemoglobin levels < 10 g/dl (P < 0.001 and < 0.05, respectively). A haemoglobin decrease < 1 g/dl during the first chemotherapy cycle, as well as a low baseline serum erythropoietin concentration, predicted a low transfusion need in rhEPO-treated patients but not in controls. During the study, 103 patients suffered at least one adverse event, but no serious, and only nine non-serious adverse events were considered possibly related to rhEPO therapy. These results indicate that treatment with rhEPO prevents anaemia, it reduces the need for blood or rhEPO erythrocyte transfusion in patients with ovarian cancer receiving platinum-based chemotherapy, and it is well tolerated. A starting dose of 150 U/kg of rhEPO, three times a week, may be recommended.

The purpose of this study was to investigate the influence of hyperthermia on cisplatin pharmacokinetics and DNA adduct formation. The latter was investigated both in tumour cell lines in vitro and in tumour cells and buccal cells from cancer patients. The patients had advanced ovarian carcinoma and were entered into a phase I study for cytoreductive surgery followed by hyperthermia in combination with intraperitoneal cisplatin administration. The cisplatin-DNA modifications in vivo and in vitro were studied by an immunocytochemical method with the polyclonal antiserum NKI-A59. The patient samples for pharmacokinetic determinations were analysed by flameless atomic absorption spectrometry. In vitro, the combination of hyperthermia and cisplatin enhanced cell killing compared with either treatment alone, such that the cisplatin-resistant ovarian cell line A2780/DDP became almost as sensitive as the parent A2780 cell line (resistance factor reduced from 30 to 2 at the IC50). In addition, increased cisplatin-DNA adducts were observed in the resistant cell line after the combined treatment compared with cisplatin alone. A good correlation was found between nuclear staining density and surviving fraction for all groups, indicating that the DNA adducts generated are an important determinant of toxicity and that the mechanism by which hyperthermia enhances kill is by increasing adduct levels. In the patients, the ratio of drug concentration in the peritoneal perfusate compared with that in plasma was found to be approximately 15, indicating a favourable pharmacokinetic ratio. Cisplatin-DNA adduct formation in tumour cells from patients was higher than in buccal cells, reflecting this higher drug exposure, i.e. local plus systemic versus systemic only. In addition, the tumour cells but not buccal cells were exposed to hyperthermia. The higher number of tumour adducts also suggests that a favourable therapeutic ratio could be achieved. Platinum-DNA adduct formation was found to decrease with distance from the surface of the tumour nodules. However, at a distance of 3-5 mm, the nuclear staining density levels were still measurable and higher than in buccal cells. In conclusion, the combined pharmacokinetic and adduct data in patients support the advantages of the intraperitoneal route for drug administration, and the addition of heat.

Purpose: To determine the maximum-tolerated dose for the combination paclitaxel and carboplatin administered every 4 weeks and to gain more insight into the pharmacokinetics and pharmacodynamics of this combination in previously untreated ovarian cancer patients., Patients and Methods: Thirty-five chemotherapy-naive patients with suboptimally debulked stage III (tumor masses > 3 cm) and stage IV ovarian cancer were entered onto this phase I trial in which paclitaxel was administered as a 3-hour intravenous (IV) infusion at dosages of 125 to 225 mg/m2 immediately followed by carboplatin over 30 minutes at dosages of 300 to 600 mg/m2. A total of six courses was planned, followed by a second-look laparoscopy/laparotomy. Patients with a response and/or minimal residual disease at second-look laparoscopy received three additional courses. Twenty-six patients participated in the pharmacokinetic part of the study., Results: The most important hematologic toxicity encountered was neutropenia. Neutropenia was more pronounced for the higher dose levels (DLs) and was cumulative. Thrombocytopenia was mild in the first eight DLs, but increased during the treatment courses. Nonhematologic toxicities consisted mainly of vomiting, neuropathy, fatigue, rash, pruritus, myalgia, and arthralgia. Dose-limiting toxicities (DLTs) in this trial were neutropenic fever, thrombocytopenia that required platelet transfusions, and cumulative neuropathy. Of 33 patients assessable for response, 26 major responders (78%, 20 complete response [CR] and six partial response [PR]) were documented. The maximal concentration (Cmax) of paclitaxel and the area under the concentration-time curve (AUC) were not different from the historical data for paclitaxel as a single agent. Retrospective analysis using a modified Calvert formula showed that the measured carboplatin AUCs in plasma ultrafiltrate (pUF) were 30% +/- 3.4% less than the calculated carboplatin AUC. Neutropenia was more pronounced than could be expected on the basis of the historical times above a threshold concentration greater than 0.1 mumol/L (T > or = 0.1 mumol/L) or 0.05 mumol/L (T > or = 0.05 mumol/L), and thrombocytopenia was less than could be expected from historical sigmoidal Emax models., Conclusion: The combination of paclitaxel 200 mg/ m2 and carboplatin 550 mg/m2 every 4 weeks is a well-tolerated treatment modality. The paclitaxel-carboplatin combination is highly active in stage III (bulky) and stage IV ovarian cancer. No indications for a pharmacokinetic drug-drug interaction between carboplatin and paclitaxel were found.

Background: Recently the feasibility of combining carboplatin with paclitaxel has been demonstrated in dose-finding studies. Maximum tolerated doses were 550 mg/m2 and 200 mg/m2 (three hours), respectively. We report now a phase II study in ovarian cancer patients., Patients and Methods: Twenty-one chemo-naïve patients with optimally (n = 6) or suboptimally (n = 15) debulked stage III or IV ovarian cancer were treated every three weeks for six courses with paclitaxel (200 mg/m2) as a three-hour infusion, immediately followed by carboplatin (550 mg/m2) as a 30-minute infusion., Results: Uncomplicated neutropenia was the principal toxicity, with mild anemia occurring regularly. As observed in the preceding phase I study, a relative lack of thrombocytopenia, generally grade III was found. Other toxicities consisted of mild neurotoxicity, nausea and vomiting, alopecia, myalgia, and bone pain. All suboptimally debulked patients responded to therapy. Overall, 12 patients underwent second-look laparoscopy, which revealed a pathologically confirmed complete remission in six. The median follow-up interval at the time of analysis was 14 months. Twelve patients are currently free of progression, at 8+ to 19 +/- months after the start of therapy., Conclusion: The carboplatin/paclitaxel combination appears to be a well-tolerated regimen, yielding high response rates. This combination has now gone forward to be evaluated in prospective randomized trials versus the cisplatin/paclitaxel combination.

The clinical pharmacology of carboplatin (C) administered with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (P) was investigated in two phase I studies undertaken in 83 previously untreated patients with either non-small cell lung cancer or ovarian cancer. Carboplatin was administered over 30 minutes and paclitaxel over 3 hours. Both agents were given every 4 weeks. Non-small cell lung cancer patients were randomized to two administration sequences, either carboplatin followed by paclitaxel (C-->P) or the reverse (P-->C). Each patient received the alternate sequence during the second and subsequent courses. Ovarian cancer patients uniformly received paclitaxel before carboplatin. Platinum concentrations in plasma ultrafiltrate were measured via flameless atomic absorption spectrometry, and 122 concentration-time curves were obtained. For non-small cell lung cancer patients, the mean area under the concentration-time curve (AUC) per 300 mg/m2 carboplatin was 3.52 mg/mL x min (range, 1.94 to 5.83) for the sequence C-->P and 3.62 mg/mL x min (range, 1.91 to 5.01) for the sequence P-->C. No sequence-dependent effect was observed (P > .5). For ovarian cancer patients, the mean AUC per 300 mg/m2 carboplatin was 3.83 mg/mL x min (range, 2.72 to 6.10), showing no difference when compared with data derived from non-small cell lung cancer patients (P = .13). In addition, the carboplatin AUC was not influenced by increasing paclitaxel doses from 100 to 250 mg/m2. Neutropenia was the principal toxicity, and anemia was frequent. However, there was a striking lack of thrombocytopenia. Modeling of the relationship between the carboplatin AUC and the decrease in platelets revealed a 50% decrease in platelets at a carboplatin AUC (AUC50) of 6.3 mg/mL x min. This contrasts with historical data documenting a carboplatin AUC50 of 4.0 mg/mL x min. Our findings suggest that there is a considerable interaction of both drugs at the cellular level, with at least an additive effect of carboplatin on the main hematologic toxicity of paclitaxel (ie, neutropenia). There is also a protective effect exerted by paclitaxel on carboplatin-related toxicity (ie, thrombocytopenia). The clear protective effect of paclitaxel in this combination suggests that it is possible to reduce the dose interval to 3 weeks. Studies are in progress to test this hypothesis and to investigate the underlying pharmacologic interactions.

Purpose: Topotecan is a topoisomerase I inhibitor with preclinical activity against various tumor types. We conducted a large multicenter phase II study with topotecan in ovarian cancer in patients who had failed to respond to one prior cisplatin-based chemotherapeutic regimen., Patients and Methods: Topotecan 1.5 mg/m2/d was administered intravenously by 30-minute infusion for 5 days repeated every 3 weeks. As the cisplatin-free interval relates to response in subsequent treatment, patients were stratified in subgroups, ie, cisplatin-refractory, cisplatin-resistant, and cisplatin-sensitive., Results: One-hundred eleven patients entered the study. Nineteen patients were considered to be ineligible; 92 patients were assessable for response. A total of 552 courses were given (median, four per patient; range, one to 17). The major toxicities were leukocytopenia and neutropenia, which were grade 3 to 4 in 54.2% and 69.1% of courses, respectively, but with only 4.3% of these being grade 4 neutropenia plus fever or infectious complications. Prophylactic granulocyte colony-stimulating factor (G-CSF) was given in 20.5% of courses to maintain dose-intensity. Other relatively frequent side effects were alopecia (82%), nausea (36.4%), and vomiting (17.5%). The overall response rate was 16.3%, with one complete response (CR) and 14 partial responses (PRs). In the cisplatin-refractory, cisplatin-resistant, and cisplatin-sensitive strata, the response rates were 5.9%, 17.8%, and 26.7%, respectively. The median duration of time of documented response was 21.7 weeks (range, 4.6 to 41.9)., Conclusion: Topotecan in a daily-times-five schedule is an effective regimen as second-line treatment in ovarian cancer. Further investigations of topotecan in ovarian cancer, including first-line use and combination with other active agents, are indicated.

Background: Changes in serum CA 125 from baseline do not reflect response to paclitaxel in relapsed ovarian carcinoma patients. Our study aimed to determine whether CA 125 changes relate to tumor response and overall survival during paclitaxel salvage treatment., Methods: Response data and CA 125 values of 77 platinum pretreated ovarian carcinoma patients were included in the study. Patients received 496 courses of paclitaxel in total (median 6; range: 2-18 courses)., Results: Response group numbers on the basis of World Health Organization (WHO) criteria were: 7 partial response, 22 stable disease, and 48 progressive disease. CA 125 values at the moment of clinical response allocation, the median survival duration, and the 3-year survival rate did not differ among WHO defined response groups. For both the stable disease group and the responders, the slopes of the exponential CA 125 regression curves during paclitaxel treatment were negative. Response groups, as defined by CA 125 changes, i.e., halving or doubling of baseline values, after 4 courses were concordant with WHO defined response groups in only 27%, but predicted survival far better., Conclusions: This study confirms that CA 125 changes in patients receiving paclitaxel treatment do not correlate with response allocations according to WHO criteria. In particular, patients with clinically and radiologically defined progression will often not show an increase in CA 125 concentrations from baseline. Those patients who do show doubling of CA 125 values, however, have a very poor prognosis. The CA 125 ratio, as determined after 4 courses of paclitaxel treatment, may be a better indicator of response than WHO defined response status.

Background: A dose-response relationship for doxorubicin in ovarian cancer (OC) cell lines has been demonstrated in vitro. However, this has never been carefully addressed in the clinic. These data and the more favourable toxicity profile of the anthracycline analogue epirubicin were reasons to study high-dose epirubicin (HDE) in OC patients who relapsed on/after platinum-based chemotherapy. This was done both in a phase I/II feasibility study (n = 27; HDE dose 120-200 mg/m2 q3 weeks) and a still ongoing straightforward phase II study (n = 91; HDE dose 150-180 mg/m2 q 3 weeks)., Results: Responses were observed at all dose levels. Overall 24 of the 118 patients responded (20%), which is much higher than reported with lower doses (7% with doses of 60-110 mg/m2). The most important side effects were myelosuppression, alopecia, nausea and vomiting and mucositis., Conclusion: HDE is tolerable and has activity in second-line after platinum-based chemotherapy in OC patients.

Purpose: Taxol (paclitaxel; Bristol-Myers Squibb, Wallingford, CT) is a new anticancer agent with activity in a number of human tumors, including epithelial ovarian cancer. In nonrandomized trials, doses studied have ranged from 135 mg/m2 to 250 mg/m2 administered over 24 hours with premedication to avoid hypersensitivity reactions (HSRs). This study addressed two questions: the dose-response relationship of Taxol in relapsed ovarian cancer and the safety of a short infusion given with premedication., Methods: Women with platinum-pretreated epithelial ovarian cancer and measurable recurrent disease were randomized in a bifactorial design to receive either 175 or 135 mg/m2 of Taxol over either 24 or 3 hours. Major end points were the frequency of significant HSRs and objective response rate. Secondary end points were progression-free and overall survival., Results: Of 407 patients randomized, 391 were eligible and 382 assessable for response. Analysis was performed according to the bifactorial design. Severe HSRs were rare (1.5% patients) and were not affected by either dose or schedule. Response was slightly higher at the 175-mg/m2 dose (20%) than at 135 mg/m2 (15%), but this was not statistically significant (P = .2). However, progression-free survival was significantly longer in the high-dose group (19 v 14 weeks; P = .02). Significantly more neutropenia was seen when Taxol was administered as a 24-hour infusion. Response rates were similar in the 24- and 3-hour groups (19% and 16%, respectively; P = .6). No survival differences were noted., Conclusion: The 3-hour infusion of Taxol is safe when given with premedication and is associated with less neutropenia. There is a modest dose effect with longer time to progression at 175 mg/m2. The observation that longer infusion produces more myelosuppression but does not yield higher response rates should lead to further studies to determine the optimal dose and schedule of this interesting new agent.

The introduction of carboplatin as a replacement for cisplatin into treatment strategies against ovarian cancer has ameliorated major toxicities related to cisplatin, but carboplatin-evoked myelosuppression requires further study, especially since the addition of growth factors for bone marrow and hematologic support has been introduced into clinical practice. Since higher doses of platinating agents seem to be related to higher response rates, the protective effect of interleukin-3 on 800 mg carboplatin, a twofold increment over the usual dose, was studied. A modest myeloprotective potency was documented in the second treatment cycle of this aggressive chemotherapy program, but this effect tapered away in subsequent treatment courses, which occasionally included severe side effects (eg, headache, kidney function impairments). Another study addressed the anemia frequently observed with both cisplatin- and carboplatin-based treatment regimens in ovarian cancer, which is probably related to low erythropoietin levels. Very preliminary analysis of an ongoing phase III trial studying two erythropoietin doses given continuously subcutaneously versus a retrospective analysis of a "control group" (drawn from historical data on the occurrence of anemia in cisplatin- and/or carboplatin-treated patients) has shown beneficial effects of erythropoietin during treatment with these platinating agents.

Patients and Methods: Twenty-one patients with metastatic ovarian cancer with minimal residual disease confined to the peritoneal cavity, were treated with intraperitoneal-administered carboplatin. Carboplatin was added to 2 liters of fluid and given via a Tenckoff-catheter. A dwell-time of 4 hours was allowed. After removal of fluid the amount of recovered carboplatin was determined., Results: It appeared that the median recovery of carboplatin was 25.5% (range 2%-56%). There was a great interpatient variability of carboplatin recovery but it was relatively constant during consecutive courses., Conclusions: Optimal dosing of intraperitoneal-administered carboplatin with a dwell-time is not possible because of the differences in recovery. This manifested itself in the fact that the absorbed dose, as well as a calculated Area Under the concentration versus time Curve (AUC), were much better related to toxicity than the administered dose.

Two clinical studies were undertaken to study the toxicity profile and effects of interleukin-3 (rhIL-3) on chemotherapy-induced myelosuppression. Fifteen patients with recurrent ovarian carcinoma were treated with high dose carboplatin (800 mg m-2). All patients received 5.0 micrograms/kg/d rhIL-3 subcutaneously but timing and duration of rhIL-3 treatment differed. Constitutional symptoms were the major toxicity and in addition to the carboplatin-induced nausea and vomiting the combination was poorly tolerated. In 5/15 patients receiving high dose carboplatin rhIL-3 administration was discontinued due to nephrotoxicity (2 x), hypotension, severe malaise and bone pain. In this study, rhIL-3 ameliorated chemotherapy-induced neutropenia as well as thrombocytopenia and reduced the requirement for platelet transfusions in the second cycle of chemotherapy. However, rhIL-3 failed to prevent cumulative platelet toxicity. In the second study 12 patients with small cell undifferentiated cancers were treated with carboplatin, etoposide and ifosfamide. Three dose levels of rhIL-3 were explored (0.125, 5.0 and 7.5 micrograms/kg/d). In this study, toxicity of the treatment was mild, however, no beneficial haematologic effects of rhIL-3 could be demonstrated. In conclusion, the haematological effects of rhIL-3 were modest and dependent on the chemotherapeutic regimen, timing and duration of rhIL-3 treatment (in relation to the expected nadir). In general rhIL-3-induced toxicity was mild, but combination with high dose carboplatin could be hazardous if rhIL-3 is initiated at 24 h after the cytostatic agent.

Purpose: To investigate the pharmacokinetics and pharmacodynamics of paclitaxel in a randomized comparative study with four different treatment arms in patients with platinum-pretreated ovarian carcinoma., Patients and Methods: Eighteen patients were entered onto this study in which paclitaxel was administered at a high dose of 175 mg/m2 versus a low dose of 135 mg/m2 on a 3- or 24-hour infusion schedule. A solid-phase extraction technique for sample pretreatment followed by a reverse-phase high-performance liquid chromatographic (HPLC) assay was used for analysis of plasma., Results: Grade 3 neutropenia occurred in all four treatment arms. However, it was more severe on the 24-hour infusion schedule. Paclitaxel concentrations as low as 0.012 mumol/L were measured with the HPLC assay. With this low quantitation threshold, we found the plasma disappearance of paclitaxel to be triphasic, with half-lives t1/2(alpha), t1/2(beta), and t1/2(gamma) mean values for the different treatment arms of 0.19 hours (range, 0.01 to 0.4), 1.9 hours (range, 0.5 to 2.8), and 20.7 hours (range, 4 to 65), respectively. Eleven possible metabolites were found, of which three were identified as taxanes by on-line HPLC-photodiode array (PDA) detection. Investigation of pharmacodynamics shows no clear relationship between the pharmacokinetic parameters area under the plasma concentration time curve (AUC), area under the plasma concentration moment curve (AUMC), maximal plasma concentration (Cmax), clearance, and toxicity. However, a relationship was found between the duration of plasma concentrations above a threshold of 0.1 mumol/L with absolute neutrophil count (ANC) and white blood cell count (WBC)., Conclusion: Paclitaxel is metabolized, and putative metabolic products can be found in plasma of patients treated with the drug. Our results indicate that myelosuppression can be predicted by the measurement of the duration of plasma concentrations above the threshold of 0.1 mumol/L.

TAXOL (paclitaxel), a new cytotoxic agent of the taxane class, has demonstrated activity against ovarian cancer. To address questions of a dose-response effect and the value of premedication to prevent hypersensitivity reactions during brief TAXOL infusions, a trial with a 2 x 2 factorial design was begun in patients with relapsed ovarian cancer. From July 1991 through March 1992, 407 patients who had failed one or two prior platinum regimens and who had measurable or evaluable disease were randomized to either 175 or 135 mg/m2 TAXOL administered by either 24- or 3-h infusion. Premedication to prevent hypersensitivity reactions, consisting of steroids, antihistamines, and H2-blockers, was administered to all patients before TAXOL. Toxicity and response data on 298 and 286 patients, respectively, are presented. Overall response rate was 18.5% (53 of 286 patients, 95% confidence interval 13.9% to 23.2%). The results suggest that TAXOL can be given safely over 3 h with premedication. Neutropenia appears to be related more to schedule than to dose, although neuropathy is primarily dose-related. Responses occurred more frequently in those who received 175 mg/m2, but analysis of all accrued patients is necessary before a final conclusion can be drawn. Studies administering TAXOL over 3 h at maximally tolerated doses are warranted.

Background: Since the introduction of the second generation platinum compound carboplatin, debate has taken place about whether this analogue can replace cisplatin in combination chemotherapy regimens for the treatment of ovarian cancer patients., Materials and Methods: In the present review the pharmacologic characteristics of carboplatin and cisplatin and the results of comparative studies are described., Results: Many of the trials performed comparing carboplatin with cisplatin, either as single agent first-line therapy or in combination chemotherapy suggest equivalent results. However, most of these trials are characterized by an inadequate patient number to detect small but important differences, inadequate carboplatin doses, ratios < 4:1, and crossover to the other analogue which makes survival comparisons difficult. Superior results in terms of either progression-free survival or overall survival have been obtained with cisplatin in two larger randomized studies of combination chemotherapy. Furthermore, another randomized study indicates substantial differences in favour of cisplatin in the subgroup of patients with < 1 cm residual tumour. Generally, there is a lack of long-term follow up., Conclusions: Based on the presently available data it is recommended that carboplatin should not routinely replace cisplatin in the management of patients with potentially curable small volume disease.

Background: Over the last few days of a 5-day international workshop held in June 1993, a group of specialists in the field of advanced epithelial ovarian cancer tried to reach consensus on a number of issues with implications for standard practice and for research., Methods: Five groups of experts considered several issues which included: biologic factors, prognostic factors, surgery, management recommendations, dose intensity, supportive care, drug resistance, second-line treatment, investigational drugs, and tumour markers. Discussing the management recommendations, the group attempted to arrive at answers to four questions: Is there in fact a cure rate for advanced ovarian carcinoma? Are there prognostic factors which help to identify patients who will not do well with current therapy? What is the current best therapy for advanced ovarian carcinoma? What directions should research take in advanced ovarian cancer? In a plenary meeting these issues were discussed., Results: Consensus statements were achieved on all topics mentioned above. This article reports on the statements written by the chairmen and approved by the consensus group.

A total of 91 eligible patients with metastatic cancer have been treated in a series of phase II trials of the novel pentacyclic pyrroloquinone, fosquidone. Tumour types were breast (24), ovary (25), head and neck (21) and melanoma (21). All patients, except those with melanoma had received prior chemotherapy. The drug was given intravenously as a 20 min infusion, at the dose of 120 mg/m2 on days 1 to 5 of a 3 week cycle. Treatment was well tolerated; the only significant side-effects being mild headaches and generalised musculo-skeletal pains. Response was assessed after 2 cycles of therapy. Only one patient (with head and neck cancer) achieved an objective partial response, lasting 6 weeks. A total of 12 patients demonstrated stable disease for a median duration of 15 to 20 weeks. Using this schedule of administration, fosquidone has no significant antitumour activity in this group of tumours.

Carboplatin-based chemotherapy has been evaluated in three studies of ovarian cancer patients. In the first, combination cisplatin and carboplatin plus doxorubicin/hexamethylmelamine/cyclophosphamide were compared as first-line treatment of ovarian cancer in 341 women with stage IIB to IV disease. There were no observed differences in results between the two treatment groups. In the second study, conventional doses of intravenous carboplatin (350 mg/m2, given on day 1) plus oral cyclophosphamide (100 mg/m2 days 2 to 6) were given to late-relapsing patients (12 to 72 months) previously treated with cisplatin. Mature data showed a 55% overall response rate, acceptable toxicity, and an absence of additive neurotoxicity. Finally, 65 patients with refractory disease or in early relapse after cisplatin therapy (within 12 months) were treated with high-dose carboplatin (800 mg/m2). Toxicity was severe, but the 45% combined response rate was considered encouraging and worthy of further evaluation. It was concluded that carboplatin is an appropriate replacement for cisplatin in the treatment of ovarian cancer.

In two studies initiated in 1979 and 1981, 377 patients were treated for advanced epithelial ovarian cancer. In the first study patients were randomly assigned to receive Hexa-CAF (hexamethylmelamine, cyclophosphamide, methotrexate, 5-fluorouracil) or CHAP-5 (cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin for 5 days) and in the second study to receive CHAP-5 or CP (cyclophosphamide, cisplatin on 1 day). Patients who did not respond to Hexa-CAF were offered subsequent treatment that included cisplatin. Median follow-up of patients in the first study was 9.5 years and in the second study 7.7 years. At 10 years 9% of the patients initially treated with Hexa-CAF and 21% of patients assigned to CHAP-5 were alive. Among the 10-year survivors treated with Hexa-CAF, 50% had experienced progressive disease but were alive as a result of retreatment with a cisplatin regimen. The survival curves of both studies revealed that approximately 60% of the patients who reached a complete remission were alive at 5 years and 40% at 10 years. Patients with microscopic disease at second-look had a less favourable outlook: 35% survived 5 years. Not recognised at first publication of both studies was the influence of tumour grade on survival. Before 5 years of follow-up, the good prognosis of grade 1 tumours (well differentiated) could not be detected. About 50% of patients with grade 1 tumours were alive at 5 and 30% at 10 years while these survival rates were halved for the other grades. Combination chemotherapy with cisplatin can enhance survival by more than 10% at 5 and 10 years compared with the best treatment of the precisplatin era: Hexa-CAF.

35 evaluable patients were treated with 5'-deoxy-5-fluorouridine (doxifluridine), a fluoropyrimidine derivative. All patients had been heavily pretreated and had refractory disease. Treatment with doxifluridine at a dosage of 3000 mg/m2 given intravenously for 5 successive days at 3-week intervals led to 6 partial remissions (17%). The main side-effects were central neurotoxicity, stomatitis and myelotoxicity, resulting in 2 toxic deaths. In patients with renal function disturbances, toxicity proved to be more severe. We concluded that the drug should not be used in patients with renal impairment. Because responses have been encountered, further evaluation of the drug may be warranted in the less toxic oral form.

A prospective study was performed in patients treated with cisplatin to evaluate the occurrence and degree of central, peripheral and autonomic neuropathy and to determine the most accurate method to study this neuropathy. Twelve patients were examined before, during and after treatment. Evaluation included neurologic examination, conventional nerve conduction studies of the median and peroneal nerves and short latency somatosensory evoked potentials (SSER) after median and tibial nerve stimulation. Valsalva maneuvers before and during treatment were performed in 11 patients. Symptoms of peripheral neuropathy paralleled clinical signs. Conventional nerve conduction studies did not seem to be more accurate than clinical examination in determining peripheral neuropathy. SSER appeared to be the most sensitive method for the detection of peripheral nerve impairment. A slowing of central conduction velocity occurred after cumulative doses of 200-400 mg/m2 as measured by SSER. In two patients also some involvement of the autonomic nerves was suggested.

In two consecutive trials, a total of 395 patients with ovarian cancer were treated with a combination of hexamethylmelamine, cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapeutic regimens including cisplatin or without this drug. With respect to neurotoxicity, 387 patients were fully eligible. The median follow-up for survival was 45 months. Neurotoxicity in any grade of severity developed in 47% of the patients treated with a cisplatin-containing regimen and in 25% of those treated with the non-cisplatin-containing regimen. The severity of neurotoxicity was much higher, however, in the cisplatin-treated patients. Neurotoxicity-free survival decreased below 50% at cumulative doses of cisplatin between 500 and 600 mg/m2. No additional effect of hexamethylmelamine on the incidence or severity of neurotoxicity could be demonstrated. In patients who survived for more than 5 years, the incidence of cisplatin neuropathy was 61%. Prognostic variables (age, International Federation of Gynecology and Obstetrics [FIGO] stage, performance status, and others) possibly associated with high-risk subgroups could not be identified. The only consistent factor correlated with neurotoxicity was the total dose of cisplatin received.

A 50-yr-old women is described with relapsed ovarian cancer. She developed neutropenic enterocolitis after treatment with high-dose carboplatin (1000 mg/m2) and granulocyte macrophage-colony stimulating factor (GM-CSF). The clinical features and the pathogenesis of neutropenic enterocolitis are discussed. This case is the first report of neutropenic enterocolitis associated with the treatment of carboplatin.

Brain metastases developed in a 40-year-old woman with relapsed ovarian cancer 2 years after cisplatin-based combination chemotherapy. After a single dose of 800 mg/m2 carboplatin, complete remission of the brain metastases occurred. A pharmacokinetic study during the second course revealed low levels of carboplatin in the cerebrospinal fluid.

The continuous 24-h infusion of ifosfamide (IFX) with mesna was studied in 44 patients with therapy-resistant or relapsing ovarian cancer. All patients had stage III disease and had been pretreated with at least one combination comprising an alkylating agent and a cisplatin analogue (22, with one combination; 16, with two; and 6, with three or more). The median number of IFX cycles received was two. Of 40 evaluable patients, 2 achieved a complete response, 5 showed a partial response and 6 had stable disease. A total of 27 patients had tumor progression after one or two treatment cycles. All seven responders had responded to previous treatment for a median duration of 5 months (range, 5-41 months). No patients who progressed during alkylating-agent treatment responded to IFX given subsequently. The median progression-free period was 6 months (range, 4-12 months), and the median overall survival was only 6 months, indicating the advanced stage of disease in these patients. The median overall survival in progressive patients was 5 months (range 2-13+ months) and that in the remaining group was 13 months (ranges 3(+)-24 months) (P less than 0.05). This treatment was moderately well tolerated. Grade 3 nausea and vomiting occurred in 27% of cycles and grade 3-4 leukopenia was observed in 47%, but thrombocytopenia was hardly ever found. In eight patients there was a deterioration of renal function. Among a total of 131 cycles, the dose was reduced for only 9 due to myelotoxicity and for 3 due to nephrotoxicity. IFX seems to be active only in patients who have relapsed after responding to previous cytotoxic treatment.

In patients with advanced ovarian cancer, initial treatment with combination chemotherapy, including cyclophosphamide and cis-platinum diamminedichloride (cis-platinum), produces response and progression-free survival results which are superior to those achieved with alkylating single-agent chemotherapy. Unfortunately most schedules have not resulted in a statistically significant improvement of overall survival. So far one of the most effective combination regimens is the four-drug regimen CHAP-5 that consists of cyclophosphamide, hexamethylmelamine, adriamycin, and cis-platinum. This regimen is the first schedule to result in significant improved survival times compared with a second combination schedule, i.e. Hexa-CAF, which is at least as good as alkylating therapy alone. The CHAP-5 regimen was rather toxic but it was manageable and easy to apply in daily practice. Further improvement of the treatment results in advanced ovarian carcinoma will be difficult because no effective new drugs are available. In future clinical research it must be tried to decrease the toxicity and morbidity of the current schedules without reducing efficacy and survival.

186 patients with advanced epithelial ovarian carcinoma were treated with either a combination of hexamethylmelamine, cyclophosphamide, methotrexate, and 5-fluorouracil (Hexa-CAF) or cyclophosphamide and hexamethylmelamine alternating with doxorubicin and a 5-day course of cisplatin (CHAP-5). Treatment with CHAP-5 resulted in more complete remissions as determined by laparatomy or peritoneoscopy (p = 0.004), better overall response (p = 0.0001), and longer overall survival and progression-free survival (p less than 0.002). Therapy, histological grade, and Karnofsky index were reliable predictors of overall response, whereas therapy, FIGO-stage, and size of residual tumour before chemotherapy were independent predictors for complete remission and for prolonged survival. Peripheral neurotoxicity was a major problem in patients assigned to the CHAP-5-group and was likely to be due to the simultaneous administration of hexamethylmelamine and cisplatin. The CHAP-5 regimen is one of the most effective regimens for the initial treatment of ovarian cancer.

Up to 30% of ovarian cancer patients with minimal residual disease may achieve a complete remission with intraperitoneal cisplatin therapy. This mode of therapy, however, is toxic and cumbersome. Sodium thiosulfate was shown to protect renal function, as well as lessen hematologic complications of cisplatin therapy. A major problem with cisplatin in terms of achieving maximal therapeutic dosages is neurotoxicity. Different platinum chemotherapeutic agents, pharmacodynamics, and pharmacokinetics of intraperitoneal administration, and rescue agents other than sodium thiosulfate are presently being investigated by The Netherlands Cancer Institute.

In patients with minimal residual ovarian carcinoma after aggressive surgical and chemotherapeutic treatment, nephrotoxicity and/or peripheral neuropathy often prohibit continued treatment with intravenous combination cisplatin-based chemotherapy. It is attractive to continue treatment of these patients with intraperitoneal (ip) delivered chemotherapy. From 1981 through 1984 a Tenckhoff catheter was implanted in 59 women for ip chemotherapy after a staging laparoscopy or laparotomy. Minor complications occurred in 8 patients and could be treated conservatively. Ten patients suffered major complications, leading to three (re)laparotomies and catheter extraction in 7 of 10 patients. No patient died of complications, but mean hospitalization time of patients with major complications was 25 days as compared to 11 days for patients without complications. An analysis of nine factors that could lead to postoperative complications failed to reveal a statistically significant risk factor. From this study no profile of a typical high-risk patient emerges.

One hundred ninety-one patients with advanced epithelial ovarian carcinoma were treated with either a combination of doxorubicin and a five-day course of cisplatin alternating with cyclophosphamide and hexamethylmelamine orally for 14 days (CHAP-5) or cyclophosphamide and cisplatin both administered intravenously (IV) on a single day at 3-week intervals (CP). At a median follow-up time of 45 months, treatment with each of these combinations resulted in the same remission rates (80% and 74%, respectively) and exactly the same progression-free survival and overall survival (median, 26 months). Despite adequate hydration, more renal toxicity was encountered in the CP-treated patients than in those who received CHAP-5. Disabling neurotoxicity and severe myelosuppression were encountered more frequently in the patients treated with CHAP-5. Because the toxicity was lower and CP treatment required shorter hospitalization, the single-day regimen was considered preferable for future use. The Karnofsky index was the only independent predictor for response, whereas both this index and the size of residual tumor before chemotherapy were predictive of survival. After correcting for other prognostic factors, it was determined that tumor size associated with improved survival was less than 1 cm. The site of metastases in International Federation of Gynecology and Obstetrics (FIGO) stage IV patients did not influence survival within this category. The results of this study confirm our previous findings that patients with microscopic remnants at second-look have a survival similar to that of patients who are histopathologically free of disease. This makes the significance of so-called pathologically confirmed complete remission questionable. The survival benefit of debulking surgery performed during chemotherapy seems only minimal for patients in whom debulking has already been attempted before treatment. Like others, we have found the CP regimen to have a good therapeutic index.

Cisplatin today is a cornerstone of combination chemotherapy for ovarian cancer. Carboplatin seems equal to cisplatin in antitumour activity, but has a different toxicity profile. After a feasibility study, a randomized phase III study in ovarian cancer stage II, III, and IV was undertaken, comparing carboplatin with cisplatin in combination with cyclophosphamide, doxorubicin and hexamethylmelamine. Preliminary analysis of this study reveals no statistically significant difference in response rate. Notwithstanding equal haematological toxicity, the other side effects evoked by carboplatin in combination treatment are much milder than those evoked by cisplatin. Further analysis will be necessary to draw definite conclusions about the results obtained.

In 23 evaluable patients with advanced ovarian epithelial cancer refractory to combination therapy with cisplatin and an alkylating agent, teniposide (VM-26) was administered as a short-term i.v. infusion at a dose of 100 mg/m2 on days 1 and 2, every 3 weeks. Toxicity was moderate and comparable to the pattern known from other studies. No objective response has been observed, showing that teniposide is not active as second-line therapy in this disease.

Sixteen patients with advanced ovarian carcinoma were treated with anaxirone (1,2,4-triglycidylurazol, TGU), 600 mg/m2 every 4 weeks. Anaxirone was the second or later line of therapy. All patients had evaluable tumors and evidence of failure of prior therapy. None of the patients responded. Two had stabilization of the disease for 4 months. In one patient WHO grade 4 leukopenia and grade 4 thrombocytopenia were observed after the second TGU cycle starting on day 41 and persisted until the patient died due to tumor progression (day 50). No patient experienced thrombophlebitis.

Based on material from two clinical trials performed by The Netherlands Joint Study Group for Ovarian Cancer, we constructed a prognostic index (PI) with considerable predictive power for long-term survival of patients treated with cytotoxic combination chemotherapy including cisplatin. The pretreatment characteristics needed for the calculation of the PI are the Karnofsky index, the site of metastases expressed as the International Federation of Gynecology and Obstetrics (FIGO) stage, the size of residual tumor, the Broders' grade, and the presence of ascites. In the subgroup comprising the 10% of the patients with the best prognosis, 4-year survival was 75%, whereas all of the patients in the subgroup comprising the 10% with the poorest prognosis died within 4 years, which illustrates the large variability of the prognosis among patients. The PI was found to retain its value after response was achieved. The information provided by the PI can be expected to be useful in treatment planning and for proper stratification of patients in clinical trials.

The study was designed to determine the efficacy of a two-drug and three-drug combination chemotherapy regimen for patients with advanced epithelial ovarian carcinoma resistant to alkylating monotherapy. Patients were randomized to receive either Adriamycin (doxorubicin) and cis-diamminedichloroplatinum(II) (AP) repeated every 3 weeks, or AP plus hexamethylmelamine (HAP) repeated every 5 weeks. Forty-five patients were evaluable for response and 49 for survival. No significant differences were found between the treatment groups as to response rate, progression-free survival, and survival. A remission was achieved in 20% of the patients and stable disease in another 20%. Median progression-free survival of all patients was only 4 months (median survival, 6 months). All patients showed progressive disease within 13 months after the onset of chemotherapy. Patients responding to treatment and those with an interval of more than 2 years between the initial diagnosis and cancer recurrence, experienced prolonged survival. Two conclusions can be drawn from the results of this study; neither of the regimens is superior to the other, and the effect of both in alkylator-resistant patients with ovarian cancer are meager. In studies on salvage chemotherapy, to the contrary, these combinations induced remissions in more than 40% of the patients. This difference in response rate might be due to differences between the prognostic factors of the patient populations. Better results are to be expected when these drugs are used in initial drug programs for previously untreated patients.